Yunan Wang

G5 PAMAM dendrimer versus liposome: A comparison study on the in vitro transepithelial transport and in vivo oral absorption of simvastatin

UNLABELLED This study compared formulation effects of a dendrimer and a liposome preparation on the water solubility, transepithelial transport, and oral bioavailability of simvastatin (SMV). Amine-terminated G5 PAMAM dendrimer (G5-NH2) was chosen to form SMV/G5-NH2 molecular complexes, and SMV-liposomes were prepared by using a thin film dispersion method. The effects of these preparations on the transepithelial transport were investigated in vitro using Caco-2 cell monolayers. Results indicated that the solubility and transepithelial transport of SMV were significantly improved by both formulations. Pharmacokinetic studies in rats also revealed that both the SMV/G5-NH2 molecular complexes and the SMV-liposomes significantly improved the oral bioavailability of SMV with the liposomes being more effective than the G5-NH2. The overall better oral absorption of SMV-liposomes as compared to SMV/G5-NH2 molecular complexes appeared to arise from better liposomal solubilization and encapsulation of SMV and more efficient intracellular SMV delivery. FROM THE CLINICAL EDITOR Various carrier systems have been designed to enhance drug delivery via the oral route. In this study, the authors compared G5 PAMAM dendrimers to liposome preparations in terms of solubility, transepithelial transport, and oral bioavailability of this poorly water-soluble drug. This understanding has improved our knowledge in the further development of drug carrier systems.

LDL Receptor Gene-ablated Hamsters: A Rodent Model of Familial Hypercholesterolemia With Dominant Inheritance and Diet-induced Coronary Atherosclerosis

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease caused mainly by LDL receptor (Ldlr) gene mutations. Unlike FH patients, heterozygous Ldlr knockout (KO) mice do not show a dominant FH trait. Hamsters, like humans, have the cholesteryl ester transfer protein, intestine-only ApoB editing and low hepatic cholesterol synthesis. Here, we generated Ldlr-ablated hamsters using CRISPR/Cas9 technology. Homozygous Ldlr KO hamsters on a chow diet developed hypercholesterolemia with LDL as the dominant lipoprotein and spontaneous atherosclerosis. On a high-cholesterol/high-fat (HCHF) diet, these animals exhibited severe hyperlipidemia and atherosclerotic lesions in the aorta and coronary arteries. Moreover, the heterozygous Ldlr KO hamsters on a short-term HCHF diet also had overt hypercholesterolemia, which could be effectively ameliorated with several lipid-lowering drugs. Importantly, heterozygotes on 3-month HCHF diets developed accelerated lesions in the aortas and coronary arteries. Our findings demonstrate that the Ldlr KO hamster is an animal model of choice for human FH and has great potential in translational research of hyperlipidemia and coronary heart disease.

Experimental Models in Syrian Golden Hamster Replicate Human Acute Pancreatitis.

The hamster has been shown to share a variety of metabolic similarities with humans. To replicate human acute pancreatitis with hamsters, we comparatively studied the efficacy of common methods, such as the peritoneal injections of caerulein, L-arginine, the retrograde infusion of sodium taurocholate, and another novel model with concomitant administration of ethanol and fatty acid. The severity of pancreatitis was evaluated by serum amylase activity, pathological scores, myeloperoxidase activity, and the expression of inflammation factors in pancreas. The results support that the severity of pathological injury is consistent with the pancreatitis induced in mice and rat using the same methods. Specifically, caerulein induced mild edematous pancreatitis accompanied by minimal lung injury, while L-arginine induced extremely severe pancreatic injury including necrosis and neutrophil infiltration. Infusion of Na-taurocholate into the pancreatic duct induced necrotizing pancreatitis in the head of pancreas and lighter inflammation in the distal region. The severity of acute pancreatitis induced by combination of ethanol and fatty acids was between the extent of caerulein and L-arginine induction, with obvious inflammatory cells infiltration. In view of the advantages in lipid metabolism features, hamster models are ideally suited for the studies of pancreatitis associated with altered metabolism in humans.

Corrigendum: Experimental Models in Syrian Golden Hamster Replicate Human Acute Pancreatitis.

Scientific Reports 6: Article number: 2801410.1038/srep28014; published online: June152016; updated: July202016 This Article contains typographical errors in the Discussion section. “Our previous study8 had proven that the local high concentration of free fatty acids in hypertriglyceridemic mice resulted in increased susceptibility to acute pancreatitis. We also had found enhanced susceptibility to acute pancreatitis in hypertriglyceridemic Syrian golden hamsters26.” should read: “Our previous study26 had proven that the local high concentration of free fatty acids in hypertriglyceridemic mice resulted in increased susceptibility to acute pancreatitis. We also had found enhanced susceptibility to acute pancreatitis in hypertriglyceridemic Syrian golden hamsters8.”

Fenofibrate nanoliposome: Preparation and its inhibitory effects on nonalcoholic fatty liver disease in mice

The aim was to prepare fenofibrate nanoliposome (FNB-Nanolipo) and investigate its characterizations, oral pharmacokinetic (PK) profiles as well as preventive and therapeutic effects on nonalcoholic fatty liver disease (NAFLD) induced by a methionine choline deficient (MCD) diet in mice. The prepared FNB-Nanolipo showed high drug loading capacity and sustained in vitro FNB release profile. Compared to FNB crude drug at equal doses, the FNB-Nanolipo given at 20 mg/kg/day (beginning on the same day when the MCD diet feeding started and lasted for 7 days) or 40 mg/kg/day (beginning after 7 days of the MCD diet feeding and lasting for another 7 days together with the MCD diet) increased plasma FNB concentration of the mice by 11.8-fold (P<0.05) or 57.3-fold (P<0.001), respectively, and reduced 54.7% (P<0.05) or 35.5% (P<0.05) of excessive hepatic lipid, respectively. The results suggest that the FNB-Nanolipo could not only significantly prevent but also efficiently treat NAFLD.

Recombinant high-density lipoproteins and their use in cardiovascular diseases.

The unique anti-atherosclerosis abilities and other cardioprotective properties make high-density lipoprotein (HDL) a promising solution in treating cardiovascular diseases. A number of studies showed that HDL-based therapy was well tolerated and has great potential in the future. Among all these new agents, the most studied ones including recombinant HDL, recombinant human apolipoproteins, apolipoprotein mimetic peptides and recombinant HDL used as contrast agents in cardiovascular imaging are discussed here. Recombinant HDL and apolipoproteins are promising in diagnosing and treating cardiovascular diseases.

Alpha-Tocopheryl Succinate-Conjugated G5 PAMAM Dendrimer Enables Effective Inhibition of Ulcerative Colitis

&NA; Ulcerative colitis (UC) is a severe inflammatory disease in colon, however, the therapeutic efficacy of the standard‐of‐care in clinic for UC patients is unsatisfactory. To explore new drugs for effective and safe treatment of UC, alpha‐tocopheryl succinate (α‐TOS) is conjugated to generation 5 (G5) poly(amidoamine) (PAMAM) dendrimer to construct a nanodevice of G5‐NH‐acetamide (Ac)‐TOS. The inhibitory effects of the G5‐NH‐Ac‐TOS on UC are evaluated in vivo in a dextran sulfate sodium induced UC mouse model, and its mechanisms are explored in vitro in lipopolysaccharide stimulated mouse peritoneal macrophages. The results indicate that the G5‐NH‐Ac‐TOS exhibits greater inhibitive effects on UC than free α‐TOS, through significant attenuation of the disease activity index and reduction of macrophage infiltration in the colon tissues. The protective mechanisms of the G5‐NH‐Ac‐TOS are revealed to be related to inhibition of expression of nuclear translocation of NF‐κB, phosphorylation of Akt, and reduction of reactive oxygen species production in the macrophages.